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      The m 6A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function

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          Abstract

          The biological functions of N6-methyladenosine (m 6A) RNA methylation are mainly dependent on the reader; however, its role in lung tumorigenesis remains unclear. Here, we have demonstrated that the m 6A reader YT521-B homology domain containing 2 (YTHDC2) is frequently suppressed in lung adenocarcinoma (LUAD). Downregulation of YTHDC2 was associated with poor clinical outcome of LUAD. YTHDC2 decreased tumorigenesis in a spontaneous LUAD mouse model. Moreover, YTHDC2 exhibited antitumor activity in human LUAD cells. Mechanistically, YTHDC2, via its m 6A-recognizing YTH domain, suppressed cystine uptake and blocked the downstream antioxidant program. Administration of cystine downstream antioxidants to pulmonary YTHDC2-overexpressing mice rescued lung tumorigenesis. Furthermore, solute carrier 7A11 (SLC7A11), the catalytic subunit of system X C −, was identified to be the direct target of YTHDC2. YTHDC2 destabilized SLC7A11 mRNA in an m 6A-dependent manner because YTHDC2 preferentially bound to m 6A-modified SLC7A11 mRNA and thereafter promoted its decay. Clinically, a large proportion of acinar LUAD subtype cases exhibited simultaneous YTHDC2 downregulation and SLC7A11 elevation. Patient-derived xenograft (PDX) mouse models generated from acinar LUAD showed sensitivity to system X C − inhibitors. Collectively, the promotion of cystine uptake via the suppression of YTHDC2 is critical for LUAD tumorigenesis, and blocking this process may benefit future treatment.

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          Highlights

          • •

            The m 6A reader YTHDC2 is frequently suppressed in LUAD and indicates poor prognosis.

          • •

            YTHDC2 suppresses the antioxidant function of system X C − via its m 6A reading domain.

          • •

            The mRNA encoding SLC7A11 is a direct target of YTHDC2.

          • •

            YTHDC2 preferentially accelerates the decay of m 6A-methylated SLC7A11 mRNA.

          • •

            LUAD with YTHDC2 suppression is sensitive to system X C − inhibitors.

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)
          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

            Suzy Torti, Donna D. Zhang, K.A. Woerpel … (2019)
            Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
            Article 0 comments Cited 2235 times – based on 0 reviews     Review now
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              Regulation of ferroptotic cancer cell death by GPX4.

              Wan Seok Yang, Rohitha SriRamaratnam, Matthew E Welsch … (2014)
              Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death. Copyright © 2014 Elsevier Inc. All rights reserved.
              Article 0 comments Cited 2123 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Lutao Du
                Yongchun Yu
                Jiayi Wang
                Journal
                Journal ID (nlm-ta): Redox Biol
                Journal ID (iso-abbrev): Redox Biol
                Title: Redox Biology
                Publisher: Elsevier
                ISSN (Electronic): 2213-2317
                Publication date PMC-release: 18 November 2020
                Publication date Collection: January 2021
                Publication date (Electronic): 18 November 2020
                Volume: 38
                Electronic Location Identifier: 101801
                Affiliations
                [a ]Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China
                [b ]Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China
                [c ]Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China
                [d ]Department of Bio-bank, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China
                [e ]Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
                [f ]Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China
                [g ]School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
                [h ]Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, 250033, Shandong province, China
                Author notes
                [∗ ]Corresponding author. NO. 247 Beiyuan Street, Jinan, 250033, Shandong province, China. lutaodu@ 123456sdu.edu.cn
                [∗∗ ]Corresponding author. No. 241 West Huaihai Road, Shanghai, 200030, China. yyc2166@ 123456sjtu.edu.cn
                [∗∗∗ ]Corresponding author. No. 241 West Huaihai Road, Shanghai, 200030, China. karajan2@ 123456163.com
                [1]

                These authors contributed equally to the work.

                Article
                Publisher Item ID: S2213-2317(20)31006-5 Publisher ID: 101801
                DOI: 10.1016/j.redox.2020.101801
                PMC ID: 7691619
                PubMed ID: 33232910
                SO-VID: 94e1f46a-c24e-489f-a55a-7fd4cb4f7dfa
                Copyright © © 2020 The Author(s)
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 4 September 2020
                Date revision received : 29 October 2020
                Date accepted : 12 November 2020
                Categories
                Subject: Research Paper

                Keywords: system xc−,cystine uptake,mettl3,lipid peroxidation,m6a rna methylation
                Data availability:
                Keywords: system xc−, cystine uptake, mettl3, lipid peroxidation, m6a rna methylation

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